Virtually all sensory information enters the neocortex by way of the thalamus. The neocortex in turn sends a massive projection back to the thalamus. Despite being reciprocally connected partners, we are only beginning to understand the nature of cortex's influence over the thalamus. It is clear that the coordinated activities of these two areas are essential for normal sensation, movement, and cognition. Moreover, altered communication between the thalamus and the neocortex has been associated with certain neurological and psychiatric disorders (e.g., absence epilepsy and schizophrenia). The central goal of my proposal is to understand the dynamic nature and mechanisms underlying corticothalamic circuits while augmenting my research training as I proceed to an independent position. There are three scientific aims in this research proposal: 1) To test the activity-dependent influence of corticothalamic output on the excitability and sensory- evoked responses of aligned thalamic neurons in the anaesthetized animal; 2) To investigate how wakefulness affects the activity-dependent influence of corticothalamic output; 3) To characterize the impact of long-range afferent systems on layer 6 circuit activity and corticothalamic output in both isolated and intact brain preparations. Under the mentorship of Drs. Barry Connors and Christopher Moore and with the support of Drs. Julie Kauer and Scott Cruikshank, I will learn new experimental techniques and develop important career skills essential for success in academia. During the K99 phase of the award, I will develop expertise in in vivo extra- and intra-cellular electrophysiological techniques, optogenetic approaches in vivo, and strategies for monitoring behavior in awake, head-restrained animals. My long-term goal is to take an interdisciplinary approach that includes newly acquired in vivo techniques as well as previously learned skills such as in vitro electrophysiology, optogenetics, two-photon microscopy, calcium imaging, glutamate uncaging, and anatomy to test my own hypotheses about corticothalamic circuitry in both isolated and intact brain preparations (R00 and beyond). My studies should help unravel some of the complexity of the corticothalamic system, and provide a mechanistic understanding of how the neocortex can control its own sensory input.